MicroRNAs (miRNAs) are small, endogenous, non-coding RNAs that are increasingly being shown to play important roles in regulating gene expression in both plants and animals. Recent reports have shown that small deletions affecting the brain-enriched miRNA, miR-137, have been identified in unrelated families with intellectual disability (ID), and SNPs in miR-137 have been linked to schizophrenia; subsequent studies have shown that reduced and over-expression of miR-137 result in defects in long-term depression (LTD), long-term potentiation (LTP), as well as learning and memory function. Since miRNAs usually have hundreds of predicted targets, it will be essential to not only identify miRNAs significant to human health, but also to identify relevant targets, and the specifics of their regulation. Although there are interesting targets of miR-137 already reported, most in vivo tests performed affect miR-137, and not the endogenous mRNA target sites; thus, it is not clear whether physiological defects resulting from loss/gain of miR-137 are due to other/additional targets. Interestingly, predicted targets of miR-137 across fly, mouse and human genomes, include multiple voltage-dependent ion channels, suggesting that miR-137 contributes to shaping the intrinsic electrical properties of neurons; these channel targets include K+ channels, Kv4/Shal (KCND1, KCND2), Shaw/Kv3 (KCNC1, KCNC3), and eag-like channels (KCNH1, KCNH7), as well as Cav3 T-type calcium channels (CACNAg, CACNAh, CACNAi). Our long-term goal is to understand if and how miR-137 regulates the intrinsic excitability of neurons, and whether mis-regulation contributes to ID and/or schizophrenia. In this R21 application, we propose to validate a system in which we can characterize how miR-137 regulates neuronal excitability, identify the affected ion channel targets, and test endogenous target site(s) in vivo. We use Drosophila as a model since available genetic tools in this system enable rapid generation of null mutants of miR-137, targeted loss/over-expression of miR-137 in subsets of neurons, as well as generation of mutations that affect endogenous target sites in the 3? UTR of individual genes. We will evaluate effects on mRNA, protein, as well as on electrical/synaptic signaling in identified neurons and eventually, on whole animal behavior. We expect molecular and cellular mechanisms to be conserved, and that our findings will provide the rationale to form and test hypotheses more efficiently in mammalian systems.